Convincing epidemiologic data indicate that inadequate sleep duration, compromised sleep quality and shift work exposure each increase the risk for weight gain, type 2 diabetes (T2D), and cardiovascular disease. In addition, controlled laboratory studies show that reduced sleep duration, sleep disruption, and circadian misalignment-typical in shift work-impair glucose metabolism. Recent genome-wide association studies have identified >20 loci associated with T2D and >15 loci associated with quantitative traits of diabetes. However, very little is known about the mechanisms by which these variants increase risk of T2D. Interestingly, two newly discovered T2D risk variants are located in the melatonin receptor gene MTNR1B and in the core circadian clock gene CRY2, providing compelling and converging support that circadian and sleep pathways play a key role in glucose metabolism. In this application, we will take advantage of existing phenotype data from epidemiologic and in-laboratory physiologic studies to investigate the physiological role of MTNR1B and CRY2 variants in sleep and circadian regulation, thereby revealing potential mechanisms by which these variants increase risk of T2D. Specifically, we will test whether MTNR1B, CRY2, and all known T2D variants are associated with phenotypes for: a) sleep physiology;b) circadian physiology;and c) glucose metabolism. These relationships will be examined in four ideal subject populations with existing, unique sleep, circadian and diabetes phenotype data in which we can also perform genotypic analysis. These data sets are complementary as they include varying sized populations with varying depth of sleep, circadian and glucose metabolism phenotypic measurements, and include (1) a large cohort study (n=6400) in which questionnaire and polysomnography-based measures of sleep physiology (duration, quality, and architecture), estimates of circadian physiology (timing of the sleep/wake cycle), and metabolic function were collected;(2,3) two diverse population-based studies (n=200, 450) that collected questionnaire and actigraphy-based measures of sleep duration and timing, and measures of metabolic function;and (4) a more selected and 'deeply-phenotyped'subject population studied throughout intensive in- laboratory sleep and circadian protocols (n=250). Results from this project will inform the experimental design of future studies in people pre-selected by genotype, as well as translational studies in the context of different environmental/behavioral exposures and pharmacological interventions (e.g. melatonin agonists). This application and the follow-up studies based on our findings should enable clinical translation of genetic discoveries for enhancing the prevention of T2D, identification of biomarkers for metabolic disease risks, and novel treatments of T2D. PUBLIC HEALTH RELEVANCE: Sleep duration, sleep quality and shift work are associated with an increased risk of type 2 diabetes. This project aims to determine the effect of type 2 diabetes genetic risk variants, particularly in the MTNR1B and CRY2 genes, on sleep, circadian and metabolic physiology as assessed in large-scale field studies and intensive in- laboratory studies. This research will provide mechanistic insights into circadian, sleep and metabolic changes that mediate increased risk of type 2 diabetes.